The formulation of lipophilic, amphipathic, or sparingly water-soluble drugs for oral administration has proven to be difficult, since in order to be absorbed, drugs need to be solubilized in the gastro intestinal fluids which are hydrous and therefore are intrinsically not favorable medium for such insoluble bioactive molecules.
Oral drug delivery vehicles must be capable of maintaining sufficient drug concentration in a bio-available form that will enable expected absorption and biological activity. Such drug delivery vehicles must also be capable of maintaining the drug in its dissolved state and maintain stability of drug and dosage form over an extended storage period while avoiding the use of physiologically harmful solvents or excipients.
Dissolved state, which enables transport of drug from the gastro intestinal fluids into the blood circulation, is a state where single drug molecules are exists individually in the fluid medium.
One approach to overcome drugs molecules self attraction and maintain hydrophobic drugs in dissolved or solubilized state at the gastro intestinal absorptive mucous is by high surfactants content delivery systems, such as, micelles, self-emulsifying micro-emulsions and related colloidal systems.
Micelles are agglomerates of colloidal dimensions formed by amphiphilic compounds or surfactants. In aqueous solution, micelles can incorporate hydrophobic therapeutic agents in the hydrocarbon core of the micelle. Loading capacity of micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant and dosage form is intrinsically of high surfactant ratio.
Another conventional approach is dissolving hydrophobic drugs in oily medium such as triglyceride-based solvents. This oily solution of lipophilic drug in oily phase may be further processed in two ways. One way is emulsifying in aqueous medium by the aid of surfactants, to produce an oil-in-water emulsion, which are inherently unstable dosage form, and second way is adding high amount of surfactant to produce thermodynamically stable micro-emulsions preferable self-emulsifying upon dilution in the gastrointestinal fluids. The properties of these oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives. Size control is a significant factor affecting absorption, smaller particles resulting in better absorption.
A further disadvantage of triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport hydrophobic therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa.
Certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis. Although recent work suggests that certain surfactant combinations, when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (U.S. Pat. No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations.
Example of self emulsifying system is described in U.S. Pat. No. 6,054,136 (Faraha et al). The invention relates to a composition which can be administered, in particular, orally, for pharmaceutical or cosmetic use, capable of forming a micro-emulsion in situ with the biological fluid of the body; the invention relates more especially to a composition providing of a self-micro-emulsifying carrier system for active agents, designated in the art by the English term “SMEDDS” (self-micro-emulsifying drug delivery system); these systems have the property of emulsifying in water at the temperature of the human body.
This composition as well as other self emulsifying compositions are intended, on the one hand to transport one or more soluble or sparingly soluble active agents, and on the other hand to form a micro-emulsion with the biological fluid of the human body, being understood that one or more active agents or principles in solution in a micro-emulsion has better bioavailability. However, the self emulsifying systems possess major drawback, of typical high surfactant content in the range of 20 to 50%.
High surfactant concentration may inhibit lipolysis and is disadvantageous to the intestinal mucous and has potential of causing local irritation side effects.
Thus, there is a need for pharmaceutical compositions that overcome the limitations of conventional micelle formulations, but without suffering from the disadvantages of triglyceride-containing formulations or disadvantage of high surfactant ratio.
A need therefore exists in the art of drug delivery to develop a vehicle that can be used with lipophilic and amphipathic insoluble materials, drugs or nutrients and that can be stored at various temperatures for extended periods of time and be dilutable or spontaneously mixing with an aqueous fluid such as blood or a buffer solution or gastro-intestinal fluids and deliver the drug to the absorption organ or membrane in a functional form.
In particularly, there is a need for such vehicle that will not comprise high and significant portion of surfactants that are irritating to the gastro intestinal mucous.
It is the objective of the present invention to furnish a carrier system for bioactive agents having limited water solubility, whereas an admixture to body fluid is possible or better dissolution and enhanced absorption is obtained while avoiding the side effects associated with high emulsifiers' concentration.
Unexpectedly, it has now been discovered that one: it is possible to formulate significant amount of hydrophobic water insoluble drugs in the low surfactant, oil in non-hydrous solvent, stable emulsion system composition, in a dissolved amorphous state, Two: good mixing of nano size droplets in the gastro intestinal fluids is obtained despite low surfactant concentration, and three: facilitate drug dissolution formulated with this system and four: maintaining stable amorphous or low crystalline state of drugs in the composition.